Global Ingredient Risk Index Botanical

Huperzine-A

Huperzine A from Huperzia serrata

Also known as: huperzine A, HupA, selagine, Huperzia serrata extract

25 მარ 2026

HIGH RISK 6.5/10 How?

This ingredient is classified as unclassified risk (GIRI score: 6.5/10).

Known Safety Concerns

FDA warning letters: not a lawful dietary supplement
Potent cholinesterase inhibitor -- nausea, vomiting, bradycardia, seizures
Interacts with cholinergic drugs and anticholinergics
Contraindicated in epilepsy, bradycardia, urinary obstruction, and GI obstruction

Contraindications

FDA warning letters: not a lawful dietary supplement
Potent cholinesterase inhibitor -- nausea, vomiting, bradycardia, seizures

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Information not yet available for this ingredient profile.

Huperzine-A is a potent acetylcholinesterase inhibitor from Chinese club moss. It is pharmacologically identical in mechanism to Alzheimer drugs (rivastigmine, donepezil). The FDA has issued warning letters stating huperzine A is not a lawful dietary supplement because it was introduced as a drug before it was sold as a supplement. Side effects include nausea, vomiting, sweating, bradycardia, and seizures at high doses.

Scientific Name: Huperzine A from Huperzia serrata

Information not yet available for this ingredient profile.

SETI Score 50/100

Risk Level High risk

Scientific Confidence Low

Evidence Strength Limited

Key Benefit Botanical

Key Safety Concern FDA warning letters: not a lawful dietary supplement

Evidence Reviewed 10 PubMed studies

Scientific Confidence Low

Based on study quality, consistency, and recency

Executive Summary — Ingredient Assessment

SETI Score 50/100

Risk Level High risk

Evidence Strength Limited

Main Benefit Botanical

Main Safety Concern FDA warning letters: not a lawful dietary supplement

Ingredient Huperzine-A

Scientific name Huperzine A from Huperzia serrata

Scientific Evidence Overview

10 studies reviewed
0 high-quality studies (meta-analysis or RCT)
Main clinical benefit observed: Botanical
Evidence consistency: High consistency across studies (100%)

Safety Signals

FDA warning letters: not a lawful dietary supplement
Potent cholinesterase inhibitor -- nausea, vomiting, bradycardia, seizures
Interacts with cholinergic drugs and anticholinergics
Contraindicated in epilepsy, bradycardia, urinary obstruction, and GI obstruction

Evidence Strength Limited

Final Scientific Assessment

The available scientific evidence for Huperzine-A indicates notable safety signals that warrant caution. Use should be considered carefully and monitored, particularly in sensitive populations or alongside other medications.

Ingredient Huperzine-A

Evidence reviewed 10 peer-reviewed studies (last 10 years)

Scientific name Huperzine A from Huperzia serrata

50 /100

Total SETI Score

High risk

Evidence quality	10/40
Evidence consistency	20/20
Safety signals	0/20
Study recency	10/10
Evidence transparency	10/10

Evidence Summary

10 studies reviewed
0 high-quality studies (meta-analysis or systematic review)
0 studies identified benefits or no safety concern (GREEN)
10 studies reported limited or advisory safety evidence (YELLOW)

Evidence Policy

Only peer-reviewed scientific literature indexed in PubMed or comparable databases is included in this evaluation. Commercial websites, blogs, and marketing materials are excluded. All references include direct traceable links to source documents.

Last updated: 25 მარ 2026, 12:55

Evidence Distribution

10 Other / unclassified

Observational / other LOW evidence YELLOW
Co-cultivationu00a0Serratia marcescens with Trichoderma harzianumu00a0for improving production of Huperzine A. ↗

PMID 41857195 ↗

Journal Appl Microbiol Biotechnol

Year 2026

Study type Observational / other

Evidence strength LOW evidence

PubMed link https://pubmed.ncbi.nlm.nih.gov/41857195/

Wen-Xia H et al.. Co-cultivationu00a0Serratia marcescens with Trichoderma harzianumu00a0for improving production of Huperzine A.. Appl Microbiol Biotechnol. 2026. PMID:41857195.
Observational / other LOW evidence YELLOW
Huperzine A improves neurological function in mice with intracerebral hemorrhage by alleviating neuroinflammation and ferroptosis. ↗

PMID 41792176 ↗

Journal Sci Rep

Year 2026

Study type Observational / other

Evidence strength LOW evidence

PubMed link https://pubmed.ncbi.nlm.nih.gov/41792176/

Wang S et al.. Huperzine A improves neurological function in mice with intracerebral hemorrhage by alleviating neuroinflammation and ferroptosis.. Sci Rep. 2026. PMID:41792176.
Observational / other LOW evidence YELLOW
Predicting cerebral acetylcholine dynamics with huperzine A pharmacokinetics in blood via mPBPK-PD modeling. ↗

PMID 41781122 ↗

Journal Chin J Nat Med

Year 2026

Study type Observational / other

Evidence strength LOW evidence

PubMed link https://pubmed.ncbi.nlm.nih.gov/41781122/

Wang J et al.. Predicting cerebral acetylcholine dynamics with huperzine A pharmacokinetics in blood via mPBPK-PD modeling.. Chin J Nat Med. 2026. PMID:41781122.
Observational / other LOW evidence YELLOW
From biosensing to herbal discovery: A nanozyme cascade platform for acetylcholinesterase monitoring and inhibitor screening in synthetic and natural sources. ↗

PMID 41687295 ↗

Journal Talanta

Year 2026

Study type Observational / other

Evidence strength LOW evidence

PubMed link https://pubmed.ncbi.nlm.nih.gov/41687295/

Cai S et al.. From biosensing to herbal discovery: A nanozyme cascade platform for acetylcholinesterase monitoring and inhibitor screening in synthetic and natural sources.. Talanta. 2026. PMID:41687295.
Observational / other LOW evidence YELLOW
Neuroinflammation as a Central Mechanism in Alzheimer's Disease: Therapeutic Insights from Schiff Base Derivatives. ↗

PMID 41683444 ↗

Journal Molecules

Year 2026

Study type Observational / other

Evidence strength LOW evidence

PubMed link https://pubmed.ncbi.nlm.nih.gov/41683444/

Abdullah SK et al.. Neuroinflammation as a Central Mechanism in Alzheimer's Disease: Therapeutic Insights from Schiff Base Derivatives.. Molecules. 2026. PMID:41683444.
Observational / other LOW evidence YELLOW
Antioxidant, Anti-Inflammatory, and Chemical Composition Analysis of In Vitro Huperzia serrata Thallus and Wild Huperzia serrata. ↗

PMID 41515488 ↗

Journal Molecules

Year 2026

Study type Observational / other

Evidence strength LOW evidence

PubMed link https://pubmed.ncbi.nlm.nih.gov/41515488/

Huang Y et al.. Antioxidant, Anti-Inflammatory, and Chemical Composition Analysis of In Vitro Huperzia serrata Thallus and Wild Huperzia serrata.. Molecules. 2026. PMID:41515488.
Observational / other LOW evidence YELLOW
Rocket-inspired gas-propelled microneedles engineered with borneol-NLCs-loaded hierarchical cavities for enhanced brain delivery in Alzheimer's therapy. ↗

PMID 41314266 ↗

Journal Int J Pharm

Year 2026

Study type Observational / other

Evidence strength LOW evidence

PubMed link https://pubmed.ncbi.nlm.nih.gov/41314266/

Shen S et al.. Rocket-inspired gas-propelled microneedles engineered with borneol-NLCs-loaded hierarchical cavities for enhanced brain delivery in Alzheimer's therapy.. Int J Pharm. 2026. PMID:41314266.
Observational / other LOW evidence YELLOW
Huperzine A associated with improved early postoperative cognitive function after neurosurgery under general anesthesia: a randomized clinical trial. ↗

PMID 41376339 ↗

Journal Int J Surg

Year 2025

Study type Observational / other

Evidence strength LOW evidence

PubMed link https://pubmed.ncbi.nlm.nih.gov/41376339/

Zhang Z et al.. Huperzine A associated with improved early postoperative cognitive function after neurosurgery under general anesthesia: a randomized clinical trial.. Int J Surg. 2025. PMID:41376339.
Observational / other LOW evidence YELLOW
Six-membered N-heterocyclic alkaloids as ChE inhibitors in alzheimer's disease treatment. ↗

PMID 41196439 ↗

Journal Metab Brain Dis

Year 2025

Study type Observational / other

Evidence strength LOW evidence

PubMed link https://pubmed.ncbi.nlm.nih.gov/41196439/

Yadav P et al.. Six-membered N-heterocyclic alkaloids as ChE inhibitors in alzheimer's disease treatment.. Metab Brain Dis. 2025. PMID:41196439.
Observational / other LOW evidence YELLOW
Research progress on plant-derived natural compounds regulating the MAPK signaling pathway for the prevention and therapy of Alzheimer's disease. ↗

PMID 41098825 ↗

Journal Front Pharmacol

Year 2025

Study type Observational / other

Evidence strength LOW evidence

PubMed link https://pubmed.ncbi.nlm.nih.gov/41098825/

Zhang X et al.. Research progress on plant-derived natural compounds regulating the MAPK signaling pathway for the prevention and therapy of Alzheimer's disease.. Front Pharmacol. 2025. PMID:41098825.

Q × L × D × S × 10 = 6.5 / 10

The GIRI Score is the product of four independently computed evidence components, each normalised to 0–1, then scaled to 0–10. Every component is derived exclusively from peer-reviewed references and regulatory data — no editorial judgement is applied.

0 of 10 approved references (score saturates at 10). More peer-reviewed studies = stronger evidence base.

Method: Q = number of approved references ÷ 10 (capped at 1.0)

50%

Limited — mostly case reports or animal studies

Method: L = mean study-level weight across approved references. Level 1 (meta-analysis / systematic review) = 1.0; Level 2 (RCT) = 0.8; Level 3 (cohort/case-control) = 0.6; Level 4 (case report) = 0.4; Level 5 (animal / in-vitro) = 0.2.

Benefit

Risk

50%

Mixed or neutral — roughly equal benefit and risk signals

Method: D = (sum of risk-scored references − sum of benefit-scored references) ÷ total evidence score, then scaled from [−1, 1] to [0, 1]. 0.0 = pure benefit; 0.5 = neutral; 1.0 = pure risk.

50%

One or more monitoring-level safety signals active

Method: S = 0.5 (neutral baseline) + sum of active signal severity deltas ÷ 10. Severity deltas: Critical = +2.0, High = +1.5, Moderate = +1.0, Low = +0.5. Capped at 1.0.

0Q × 5L × 5D × 5S = 6.5 / 10

Final GIRI Score for Huperzine-A. Risk level thresholds: Low 0–3.0 · Moderate 3.0–5.5 · High 5.5–7.5 · Critical 7.5–10.

Full methodology & data sources

The GIRI Score is computed entirely from structured data — no editorial scoring or subjective weighting is applied at any step.

References: Only approved references are counted. Each reference is assigned an evidence level (L1–L5) and a direction (risk / neutral / benefit) by the reference manager or AI classifier.
Safety Signals: Sourced from regulatory agencies (FDA, EMA, Health Canada, TGA, and others) and pharmacovigilance databases. Only active signals count toward the score.
Formula version: GIRI Score v3.7.0 — Q × L × D × S × 10.
Limitations: The score reflects published evidence and recorded signals as of the last update date. It is not a clinical risk assessment and should not replace advice from a qualified healthcare professional.

HIGH RISK 6.5/10

Based on available regulatory signals and scientific evidence, this ingredient presents a high safety concern. Its use in dietary supplements is associated with documented adverse events.

LOW
0–3.0

MODERATE
3.0–5.5

HIGH
5.5–7.5

CRITICAL
7.5–10

6.5

The score pin shows exactly where this ingredient falls on the fixed risk scale.

What drove the High classification for Huperzine-A

A score of 6.5 places this ingredient in the High band. Thresholds: Low 0–3.0 · Moderate 3.0–5.5 · High 5.5–7.5 · Critical 7.5–10.

0 approved references.

Limited — mostly case reports or animal studies (Level 4–5).

Neutral or mixed — benefit and risk signals roughly balanced.

No active signals — S component is at neutral baseline (0.5), contributing no extra risk weight.

No major regulatory restrictions or advisories recorded across monitored jurisdictions (FDA, EMA, Health Canada, TGA, and others).

How are the Low / Moderate / High / Critical thresholds defined?

The four risk levels are fixed score bands. A score is assigned to exactly one level based on where it falls:

Level	Score	Meaning
LOW	0.0 – 2.9	Sparse or predominantly beneficial evidence. No active safety alerts.
MODERATE	3.0 – 5.4	Mixed signals — some risk alongside benefit. Caution at high doses or in sensitive groups.
HIGH	5.5 – 7.4	Multiple studies or regulatory alerts documenting adverse effects. Professional oversight recommended.
CRITICAL	7.5 – 10	Regulatory restrictions in one or more major jurisdictions. Serious documented harm. Avoid without specialist supervision.

Thresholds are fixed constants (GIRI_Score_Utils::LEVEL_THRESHOLDS). They do not change per ingredient and are never subject to editorial adjustment.

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Huperzine-A

Safety Profile

Known Safety Concerns

Contraindications

Interactions

Evidence and Scientific Findings

Ingredient Overview

Biological and Chemical Classification

Mechanism of Action

Clinical Evidence of Effectiveness

Pharmacokinetics

Recommended Dosage

SETI — Scientific Evidence Transparency Index

Executive Summary — Ingredient Assessment

Evidence Summary

Evidence Policy

Evidence Distribution

Score Transparency

Risk Level Classification

What drove the High classification for Huperzine-A

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